Certain 10,11-bis(bromomethyl)-dibenzazepines

ABSTRACT

COMPOUNDS OF THE CLASS OF 1,2,3,8-TETRAHYDRO-DIBENZO(B,F)PYRROLO(3,4-D)AZEPINES AND PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF HAVE A DEPRESSANT EFFECT ON THE CENTRAL NERVOUS SYSTEM; THEY CAN BE PREPARED FROM N-SUBSTITUTED 10,11 - BIS - BROMOMETHYL - 5H - DIBENZ(B,F)AZEPINES AND A PRIMARY AMINE; THE COMPOUNDS ARE ACTIVE INGREDIENTS OF PHARMACEUTICAL COMPOSITIONS; AN ILLUSTRATIVE EMBODIMENT IS 2-ETHYL - 1,2,3,8 - TETRAHYDRODIBENZO (3,4-D) AZEPINE.

United States Patent 3,786,045 CERTAIN 10,11-BIS(BROMOMETHYL)-DIBENZAZEPHWES Hans Blattner and Walter Schindler, Riehen, near Basel,Switzerland, assignors to Ciba-Geigy Corporation, Ardsley, N.Y.

No Drawing. Original application Nov. 19, 1969, Ser. No. 878,177, nowPatent No. 3,646,046. Divided and this application Sept. 18, 1972, Ser.No. 290,033

Claims priority, application Switzerland, Dec. 19, 1968, 18,946/ 68 Int.Cl. C07d 41/08 U.S. Cl. 260--239 D 1 Claim ABSTRACT OF THE DISCLOSURECompounds of the class of 1,2,3,S-tetrahydro-dibenzo-[b,f]pyrrolo[3,4-d]azepines and pharmaceutically acceptable acidaddition salts thereof have a depressant effect on the central nervoussystem; they can be prepared from N-substituted 10,11 bis bromomethyl Hdibenz[b,f]azepines and a primary amine; the compounds are activeingredients of pharmaceutical compositions; an illustrative embodimentis Z-ethyl l,2,3,8 tetrahydrodibenzo 3,4-d] azepine.

This is a division, of application Ser. No. 878,177, filed Nov. 19,1969, now U.S. Pat. 3,646,046.

DETAILED DESCRIPTION The present invention relates to new azepinederivatives, processes for the production thereof, medicamentscontaining the new compounds and their use.

More particularly, the present invention concerns compounds of Formula I1120/ CHg wherein R is hydrogen, methyl, ethyl or propyl, and R ishydrogen, straight chain lower alkyl with 1 to 4 carbon atoms, isopropylor allyl,

as well as pharmaceutically acceptable acid addition salts thereof.

As straight chain lower alkyl, R can be the methyl, ethyl, propyl orbutyl group.

A preferred class are compounds of Formula I, wherein R is a straightchain lower alkyl having 1 to 4 carbon atoms, isopropyl or allyl and thepharmaceutically acceptable acid addition salts thereof.

Preferred members are:

2-ethyl-1,2,3,8-tetrahydro-dibenzo [b,f]pyrrolo [3,4-d]

azepine;

2-allyl-1,2,3, E-tetrahydro-dibenzo [b,f] pyrrolo 3,4-d]

azepme;

2-butyl-1,2,3,8-tetrahydro-dibenzo [b,f]pyrrolo [3 ,4-d]

azepine;

2-ethyl-8-methy1-L2, 3 8-tetrahydro dibenzo[b,f]pyrrolo- [3,4-d1azepine;

and the pharmaceutically acceptable acid addition salts thereof.

3,786,045 Patented Jan. 15, 1974 E BrBrH in an (III) wherein R has themeaning given under Formula I, hydrolyzing the reaction product, if R isa group which, by means of hydrolysis, can be replaced by hydrogen, andoptionally converting an obtained compound of Formula I with aninorganic or organic acid into an addition salt.

The bis-bromomethyl compounds of Formula II are reacted with the freebases of Formula III in the presence of a solvent. Suitable solvents arethose which are inert under the reaction conditions, e.g. hydrocarbonssuch as benzene or toluene, halogenated hydrocarbons such as chloroform,lower alkanols such as methanol or ethanol, ether-like solvents such asether or dioxane, as Well as lower alkanones such as acetone,methylethyl ketone or diethyl ketone.

In the reaction, according to the invention, of one molar equivalent ofthe bis-bromomethyl compounds with one molar equivalent of free bases,two molar equivalents of hydrogen bromide are split off and preferablybound by the use of excess base of Formula III.

Groups R convertible by hydrolysis into the hydrogen atom, are, forexample, acyl groups, e.g. lower alkanoyl groups such as the acetylgroup, arylcarbonyl groups such as the benzoyl group, groups ofmonofunctional derivatives of carbonic acid such as, e.g. themethoxycarbonyl, ethoxycarbonyl or the phenoxycarbonyl group. Thehydrolysis can be performed with the aid of an alkali metal hydroxide,e.g. potassium or sodium hydroxide, preferably at the boilingtemperature, either in a higher boiling organic solvent containinghydroxyl groups such as, eg ethylene glycol or diethylene glycol, or ina lower monoalkyl ether of such a glycol and, in particular, in a loweralkanol, e.g. methanol or ethanol. M0reover, the hydrolysis can becarried out, e.g. in acid medium, e.g. in alkanolic hydrochloric acid,or with the aid of hydrogen bromide in Water or glacial acetic acid.

One starting material of Formula II, the S-methyl-lO,11-bis-bromornethyl-5H-dibenz[b,f]azepine, is obtained, for example, asfollows: 5-methyl-5,11-dihydro-10H- dibenz[b,f]azepin-10-one isconverted with sodium amide into the ll-sodium derivative which in turnis methylated with methyl iodide to give the 5,1l-dimethyl-5,11-dihydro-10H-dibenz[b,f]azepine-lO-one. The methylation product yields withmagnesium and methyl iodide, according to 3 the Grignard reaction, the5,10,1l-trimethyl-10,11-dihydro-H-dibenz[b,f] azepin-lO-ol, which isdehydrated, using polyphosphoric acid, to obtain the 5,10,11-trimethy1-5H-dibenz[b,f]azepine. Finally, the reaction product is brominated withN-bromosuccinimide.

A group of starting materials of Formula II are compounds which aresubstituted in the 5-position by an acyl group, e.g. the acetyl group,the methoxycarbonyl or ethoxycarbonyl group. The 5acetyl-l0,11-bis-bromomethyl-5H-dibenz[b,f]azepine is obtained, e.g. byacylating 10,11-dimethyl-5H-dibenz[b,f]azepine (cp. Geigy A.G. US. Pat.No. 3,130,191) with acetyl chloride and brominating the obtained5-acetyl-10,1l-dimethyl-SH- dibenz[b,f]azepine with N-bromosuccinimide.Further S-acyl derivatives of Formula H can be produced analogously.

A second process according to the invention for the production ofcompounds of Formula I comprises alkylating a compound of Formula IV 11:Hz 0 CHg in which R has the meaning given under Formula I by means of areactive ester of an alkanol of Formula V in which R has the meaning ofR given under Formula I with the exception of hydrogen, preferably inthe presence of a solvent and a basic condensing agent and, if desired,converting the compound of Formula I thus obtained into an acid additionsalt thereof with an inorganic or organic acid.

Starting materials of Formula IV are prepared analogously to the firstprocess by reacting S-substituted-lO, l1 bis-bromomethyl-SH-dibenz[b,f]azepine compounds of Formula II, wherein R is a group which by means ofhydrolysis can be replaced by hydrogen, with an amine of Formula III andsubsequently hydrolyzing the acyl compounds thus obtained. Thehydrolyzable groups at the '5-position and the methods for hydrolyzingthem are the same as mentioned in the first process.

A third process for the preparation of compounds of Formula I comprisesreducing a compound of Formula VI wherein R has the meaning given underFormula I and R is an alkanoyl group, with diborane in ethereal solutionand, if desired, converting a compound of Formula I thus obtained intoan addition salt thereof with an inorganic or organic acid.

Suitable as reaction media are, for example, tetrahydrofuran, dioxane,methyleneglycoldimethylether or diethyleneglycolmethylether. Thereaction temperature is preferably between room temperature and about100 and reaction time preferably between about 30 minutes and 25 hours.The diborane is prepared, for example, from borontrifluorideetherate andsodium borohydride ether in situ or in a separate apparatus andsubsequently added to the reaction mixture.

Starting materials of Formula VI in which R as alkanoyl group can be theformyl, acetylor propionylgroup are prepared according to the firstprocess and according to the process for the preparation of the startingcompounds of Fomula IV by reacting5-alkanoyl-l0,llbis-bromomethyl-SH-dibenz[b,f]azepine compounds ofFormula II with an amine of Formula III.

5 alkanoyl-10,11=bis-bromomethyl-5H-dibenz[b,f]azepine compounds ofFormula II are obtained, for example, by acylating10,1l-dimethyl-SH-dibenz[b,f]azepine (cf. Geigy A.G. US. Pat. No.3,130,191) with an alkanoyl chloride to give 5-alkanoyl-1'0,ll-dimethyl-SH-dibenz [bf] azepine and then brominating the reactionproduct with N-bromosuccinimide.

A fourth process for the preparation of compounds of Formula I compriseshydrolyzing a compound of Formula VII in which R has the meaning givenunder Formula I, and Ac is the acyl group of an organic acid and, ifdesired, converting a compound of Formula I into an addition saltthereof with an inorganic or organic acid.

In the starting material of Formula VII, Ac is in particular the acylgroup of cyanic acid, chloroformic acid, a carbonic acidor thiocarbonicacid mono-ester, a lower alkanoic acid or an arene carboxylic acid.Examples of acyl groups Ac are the cyano-, chlorocarbonyl-,methoxycarbonyl-, ethoxycarbonyl-, tert.butoxycarbonyl,phenoxycarbonyl-, benzyloxycarbonyl-, methoxythiocarbonyl-,methylthio-thiocarbonyl, acetyland the benzoyl group.

The hydrolysis of compounds of Formula VII is carried out, for example,by heating such compounds for several hours in an alkanolic oraqueous/alkanolic solution of an alkali metal hydroxide, for example, byboiling in a mixture of potassium or sodium hydroxide with ethanol ormethanol and a little water. Apart from alkanol, other solventscontaining a hydroxyl group may be used, such as ethylene glycol andmonoalkyl esters thereof. Furthermore, compounds of Formula VII, inparticular those in which Ac is the acyl group of cyanic acid, can behydrolyzed by heating with a mineral acid in an organic/ aqueous oraqueous medium, for example, by boiling for several hours in a mixtureof phosphoric acid and formic acid or by heating for several hours in48% hydrobromic acid at 60 to 70.

The starting material of Formula VII is itself prepared by reacting acompound of Formula VIII (VIII) ester, the chloroformic acid phenylester or -benzy1 ester, a chloride or bromide of a lower alkanoic orbenzoic acid, in particular acetyl chloride, acetylbromide orbenzoylchloride, at room temperature or a raised temperature, whereby,according to the Von Braun reaction, the desired acylation occurs withthe splitting off of the group R The reaction is carried out in an inertorganic solvent such as, for example, chloroform or benzene or, ifdesired, also in an excess of an acylhalide suitable as reaction medium.

The starting material of Formula VIII is prepared by reacting a compoundof Formula II with an amine of Formula IX 4 III-H in which R, is loweralkyl, allyl or benzyl, whereby similar reaction conditions are appliedas described in the first process of the present invention.

The compounds of Formula I may optionally be converted, in the usualmanner, into their pharmaceutically acceptable acid addition salts withinorganic and organic acids. For example, the acid desired as saltcomponent, or a solution of the acid, is added to a solution of acompound of Formula I in an organic solvent. For the reaction, it ispreferable to use organic solvents, in which the salt formed is notreadily soluble, so that it can be separated by filtration. Suchsolvents are, e.g. methanol, acetone, methyl ethyl ketone, acetone/ethanol, methanol/ ether or ethanol/ether.

Pharmaceutically acceptable acid addition salts are derived from suchacids, the anions of which are non-toxic at the required dosage levels.Furthermore, it is of advantage if the salts to be used as medicamentsreadily crystallize and are not, or are only slightly hygroscopic. Forsalt formation with compounds of Formula I, it is possible to use, e.g.hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,methanesulfonic acid, ethanesulfonic acid, fi-hydroxyethanesulfonicacid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid,oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid,salicylic acid, phenylacetic acid, mandelic acid and embonic acid.

The depressant effect of the compounds of the invention on the centralnervous system is demonstrated in a variety of standard animal test [cp.R. Domenjoz and W. Theobald et al., Arch. int. Pharmacodyn. 120, 450(1959), and W. Theobald and and R. Domenjoz, Arzneimittelforschung 8, 18(1958)]. In particular, it is demonstrated that the compounds of FormulaI and the pharmaceutically acceptable acid addition salts thereof onoral, rectal or parenteral administration in amounts of from about 0.1to about 20 mg./kg. to such test animals as mice and rats reducemotility, potentiate the action of analgesics and anesthetics,counteract the effect of amphetamine, exhibit a positive action in thetest de la traction, have an antiemetic, serotonin-antogonistic actionand lower the body temperature. Also an antihistamic effect can beobserved. The toxicity of the compounds of the invention is of favorablelow order.

For their intended use in mammals, the compounds of the invention areadministered in daily dosages of between 0.1 mg./kg. and 10.5 mg./kg.The exact dosages depend of course on the species, age and weight of theindividuum under treatment as well as on the particular condition beingtreated and the form of administration.

Suitable dosage units such as drages, tablets, suppositories orampoules, preferably contain 520() mg. of an active substance, accordingto the invention, or of a pharmaceutically acceptable salt thereof.

Dosage units for oral administration preferably contain as activesubstance between 1 and 90% of a compound of Formula I or of apharmaceutically acceptable salt thereof. They are produced by combiningthe active substance with, e.g. solid, pulverulent carriers such aslactose, saccharose, sorbitol, or mannitol; starches such as potatostarch, maize starch or amylopectin, also laminaria powder or citruspulp powder; cellulose derivatives or gelatine, optionally with theaddition of lubricants such as magnesium stearate or calcium stearate orpolyethylene glycols, to form tablets or drage cores. The drage coresare coated, e.g. with concentrated sugar solutions, which can alsocontain, e.g. gum arabic, talcum and/or titanium dioxide or with alacquer dissolved in easily volatile organic solvents or mixtures ofsolvents. Dyestuffs can be added to these coatings, e.g. to distinguishbetween varying dosages of active substance.

Other suitable dosage units for oral administration are hard gelatinecapsules as well as soft, closed capsules made from gelatine and asoftener such as glycerin. The hard capsules preferably contain theactive substance as a granulate, e.g. in admixture with fillers such asmaize starch, and/or lubricants such as talcum or magnesium stearateand, optionally, stabilizers such as sodium metabisulphite (Na S O orascorbic acid. In soft capsules, the active substance is preferablydissolved or suspended in suitable liquids such as liquid polyethyleneglycols, whereby stabilizers can also be added.

Suitable dosage units for rectal administration are, e.g. suppositoriesconsisting of a combination of an active substance, or of a suitablesalt thereof, with a fatty foundation substance. Also suitable aregelatine rectal capsules containing a combination of the activesubstance, or of a suitable salt thereof with polyethylene glycol.

Ampoules for parenteral, especially intramuscular administration,preferably contain a water-soluble salt of an active substance in aconcentration of preferably 0.5 to 5%, optionally together with suitablestabilizing agents and buffer substances, in aqueous solution.

The following examples further illustrate the nature of the presentinvention but they should not be construed as a limitation of the scopethereof. The temperatures are given in degrees centigrade.

Example 1 (a) 35 g. of 5-acetyl-10,ll-bis-bromomethyl-SH-dibenz-[b,f]azepine are dissolved in 250 .ml. of anhydrous benzene. Theobtained solution is added dropwise within one hour at 5l5 to a solutionof 20 g. of methylamine in 180 ml. of anhydrous benzene. The reactionmixture is stirred for a further hour at 40, cooled to 20 and 25 ml. ofwater are added all at once. The organic phase is separated, dried overpotassium carbonate and completely concentrated by evaporation in arotary evaporator. The residue, the Z-methyl 8acetyl-1,2,3,8-tetrahydro-dibenzo[b,f]pyrrolo[3,4-d]azepine, is aviscous oil which, as crude product, is further processed.

(b) 23 g. of 2methyl-8-acetyl-l,2,3,8-tetrahydrodibenzo[b,f]pyrrolo[3,4-d]azepine(crude product) are refluxed with 115 ml. of 20% ethanolic potassiumhydroxide solution for 2 hours. The mixture is then cooled to 20 and theprecipitated crude product is filtered with suction. The obtained2-methyl l,2,3,8 tetrahydro-dibenzo[b,f] pyrrolo[3,4-d]azepine melts,after recrystallization from benzene, at 233234; 14 g. of the obtainedbase are stirred into ml. of anhydrous acetone and the hydrochloride isprecipitated with 11.3 ml. of 5 N anhydrous ethanolic hydrochloric acid;M.P. of the hydrochloride after recrystallization from ethanol is233236.

The starting material, the5-acetyl-10,l1-bis-bromomethyl-5H-dibenz[b,f]azepine, is produced asfollows:

(c) 39.5 g. of acetyl chloride are added dropwise within 30 minutes,whilst stirring, to a solution of 98 g. of10,1l-dimethyl-5H-dibenz[b,f]azepine (cp. Geigy A.G., US. Pat. No.3,130,191), M.P. 131-132", in 295 ml. of toluene. The reaction mixtureis afterwards refluxed for 5 hours, concentrated by evaporation in vacuoand the residue dissolved in ether. The ethereal solution is washed withwater, dried over sodium sulphate and concentrated by evaporation. Theresidue, which is recrystallized from petroleum ether, yields the5-acetyl-10,1I-dimethyl-SH-dibenz[b,f] azepine M.P. 109111.

(d) 1 01 g. of 5-acetyl-10,11-dimethyl-5H-dibenz[b,f] azepine aredissolved in one litre of carbon tetrachloride and to the solution areadded 138 g. of N-bromosuccinimide. By exposure to two 200 watt lamps orto a UV- lamp, the mixture is heated, while being stirred, to boiling.The mixture is kept boiling until all the N-bromosuccinimide isconverted. The reaction mixture is cooled to and 200 ml. of water areadded. The precipitated crystallineacetyl-10,11-bis-bromomethyl-5H-dibenz[b,f] azepine, M.P. 175176, isfiltered with suction.

Example 2 Analogously to Examples 1 (a) and (b) are produced thefollowing intermediate products and final products:

(a) From 23 g. of 5-acetyl-10,1l-bis-bromomethyl-SH- dibenz[b,f]azepineand g. of ethylamine in 135 ml. of anhydrous benzene is obtained theintermediate product: 2-ethyl-8-acetyl-1,2,3,8-tetrahydrodibenzo[b,f]pyrrolo- [3,4-d] azepine (crude product); and by subsequentsaponification is obtained the final product:2-ethyl-1,2,3,8-tetrahydro-dibenzo [b,f]pyrrolo[3,4-d] azepine, M.P.209-21 1 (from benzene); hydrochloride M.P. 260-264 (from ethanol).

(b) From 37.5 g. of 5-acetyl-l0,ll-bis-bromomethyl-5H-dibenz[b,f]azepine and 15 g. of propylamine in 135 ml. of anhydrousbenzene is obtained the intermediate product: 2-propyl-8-acetyl-1,2,3,8tetrahydro dibenzo- [b,f]pyrrolo [3,4-d]azepine (crude product); and bysubsequent saponification is obtained the final product. 2-propyl1,2,3,8-tetrahydro dibenzo[b,f]pyrrolo[3,4-d]azepine, M.P. 181-182 (frombenzene); hydrochloride, M.P. 253256 (from ethanol).

(c) From 37.5 g. of acetyl-10,1l-bis-bromomethyl-SH- dibenz[b,f]azepineand 15 g. of allylamine in 135 ml. of anhydrous benzene is obtained theintermediate product: 2-allyl-8-acetyl 1,2,3,8tetrahydro-dibenzo[b,f]pyrrolo- [3,4-d] azepine (crude product); and bysubsequent saponification is obtained the final product:2-allyl-1,2,3,8-tetrahydro dibenzo[b,f]pyrrolo[3,4 d]azepine, M.P. l74176 (from benzene); hydrochloride, M.P. 245249 (from ethanol); and

(d) From 25 g. of 5-acetyl-l0,ll-bis-bromomethyl-SH- dibenz[b,f]azepineand 26 g. of butylamine in 150 ml. of anhydrous benzene, theintermediate product 2-butyl-8- acetyl 1,2,3,8 tetrahydrodibenzo[b,f]pyrrolo[3,4-d] azepine (crude product); and by subsequentsaponification, the end product 2-butyl-1,2,3,8-tetrahydro-dibenzo-[b,f]pyrrolo[3,4-d]azepine, M.P. 156-157 (from ethanol); hydrochloride,M.P. 230234 (from ethanol).

(e) From 29.5 g. of 5-acetyl-10,11-bis-bromomethyl-5H-dibenz[b,f]azepine and 22 g. of isopropylamine in 150 ml. ofanhydrous benzene, the intermediate product 2-isopropyl-8-acetyl-1,2,3,8tetrahydro dibenzo[b,f]pyrrolo- [3,4-d]azepine (crude product); and bysubsequent saponification, the end product2-isopropyl-1,2,3,8-tetrahydro-dibenzo[b,f]pyrrolo[3,4-d]azepine, M.P.197198 (from benzene); methanesulphonate, M.P. 282-285 (from ethanol).

Example 3 (a) 14 g. of 5-methyl-l0,11-bis bromomethylSH-dibenz[b,f]azepine are dissolved in 60 ml. of anhydrous benzene andthe solution is added dropwise within one hour at 3234, whilst stirringis maintained, to a solution of 30 g. of methylamine in 270 ml. ofmethanol. The reaction mixture is stirred for a further one hour at 50and the solvent and excess methylamine are then distilled otf. 50 ml. ofwater are added to the residue and the suspension is extracted withether. The etheral solution is Washed with water and extracted with 2 Nhydrochloric acid. The acid aqueous extract is rendered alkaline tophenolphthalein with concentrated ammonia water and the precipitatedbase extracted with ether. The ethereal solution is washed with water,dried over potassium carbonate and concentrated by evaporation. theresidue, the 2,8-dimethyl-1,2,3,8 tetranydro dibenzo[b,f]pyrrolo[3,4-d]azepine, is recrystallized from petrol and melts at 121"; oxalate, M.P.230232.

The Starting material, the5-methyl-10,ll-bis-bromomethyl-5H-dibenz[b,f]azepine, is produced asfollows:

(b) A suspension of 43 g. of sodium amide in 120 m1. of toluene is addeddropwise within one hour at 6575, whilst vigorous stirring ismaintained, to a solution of 223 g. of5-methyl-5,11-dihydro-10H-dibenz[b,f] azepinl0-one in 1.5 litres ofanhydrous benzene. The reaction mixture is subsequently refluxed for 2hours. The suspension is afterwards cooled to 45-50, 221 g. of methyliodide are added dropwise within 2 hours at this temperature andstirring is maintained for a further 16 hours at 4550. The reactionmixture is cooled to 5l0 and to it are carefully added 250 ml. of water.The organic phase is separated, washed with water, dried over sodiumsulphate and concentrated to ca. 400 ml. To this concentrated solutionare added 200 ml. of petroleum ether, whereupon the5,1l-dimethyl-S,ll-dihydro-lOH-dibenz- [b,f]azepin-10-one, M.P. 128430",crystallizes out.

(o) A solution of 228 g. of 5,11dimethyl-5,11-dihydro-1OH-dibenz[b,f]azepin-lO-one in 950 ml. of anhydrous benzene is addeddropwise within 1 /2 hours, with vigorous stirring, to a Grignardsolution prepared from 47 g. of magnesium and 273 g. of methyl iodide in540 ml. of absolute ether, whereby a reaction temperature of 5 to 0 ismaintained. The suspension is subsequently heated to 50 and stirringproceeds for a further 20 hours at this temperature. The reactionmixture is cooled to 0 and then poured on to a mixture of one litre of 2N hydrochloric acid and 500 g. of ice. The organic phase is separatedand the aqueous phase again extracted with benzene. The combined organicsolutions are washed with water, dried over sodium sulphate andconcentrated by evaporation in vacuo. The residue, which isrecrystallized from petrol yields the 5,10,]1-trimethyl-10,1l-dihydro-5H-dibenz[b,f]azepin-lO-ol, M.P. 102-104";

((1) A mixture of 89 g. of5,10,11-trimethyl-10,11-dihydro-5H-dibenz[b,f]azepin-lO-ol and 890 g. ofpolyphosphoric acid is well stirred for one hour at 95-100. The reactionmixture is cooled to 6070 and slowly poured on to 3 litres of water at40, so that the reaction temperature does not exceed 6070. Theprecipitated product is filtered with suction at 20, one litre of 2Nammonia solution is added and the liberated base is extracted withbenzene. The benzene solution is Washed with Water, dried over potassiumcarbonate and concentrated by evaporation. The residue, which isrecrystallized from petrol yl gegldsi 1tii e5,10,11-trimethyl-5H-dibenz[b,f]azepine, M.P.

(e) 23.5 g. of 5,10,1l-trimethyl-SH-dibenz[b,f]azepine are dissolved in300 ml. of carbon tetrachloride and to the solution are added 36 g. ofN-bromosuccinimide. Whilst being stirred and exposed to two 200 wattlamps, or to a UV-lamp, the mixture is heated to boiling. The mixture ismaintained boiling until all the N-bromosuccinimide is converted. Thereaction mixture is then cooled to 20 and 50 m1. of water are added. Theorganic phase is separated, washed with water, dried over sodiumsulphate and concentrated by evaporation at 40 in vacuo. The residue isdissolved in 50 ml. of ether, the solution cooled to 0, whereupon the5-methyl-10,1l-bis-bromomethyl-SH-dibenz[b,f] azepine, M.P. 127130,crystallizes out.

Example 4 The following end products are prepared analogously to Example3 (a).

(a) From 16 g. of 5-methyl-10,ll-bis-bromomethyl- 5H-dibenz[b,f]azepineand 25 g. of ethylamine in ml. of methanol. the2-ethyl-8-methyl-1,2,3,8-tetrahydrodibenzo[b,f]azepine (crude product);oxalate, M.P. 208- 210 (from methanol).

(b) From 39.5 g. of 5-methyl-10,1l-bis-bromomethyl-5H-dibenz[b,f]azepine and 28.5 g. of allylamine in 100 m1. of methanol,the2-allyl-8-methyl-1,2,3,8-tetrahydrodibenzo[b,f]pyrrolo[3,4-d]azepine,M.P. 137-139" (from anhydrous ethanol). Methanesulfonate, M.P. 194-196(from anhydrous ethanol).

Example 5 (a) To a suspension of 7.8 g. of2-ethyl-1,2,3,8-tetrahydro-dibenzo[b,f]pyrrolo[3,4-d1azepine in 40 ml.of dimethyl formamide are added 0.8 g. of sodium hydride at atemperature of 25-35".

The reaction mixture is then stirred for a further hour at 80, cooled to20 and at this temperature a solution of 5.1 g. of propyliodide is addeddropwise Within 30 minutes. The reaction mixture is then stirred for 18hours between 50 and 55, cooled to 20 and water and ether then added.The organic phase is separated and extracted with 2N hydrochloric acid.

The free base is precipitated out from the hydrochloric acid extractwith concentrated ammonia water and taken up with ethyl ether. Theethereal solution is washed with water, dried over potassium carbonateand completely evaporated in a rotary evaporator. The residue yields,after recrystallization from ethanol, 2-ethyl-8-propyl-l,2,3,S-tetrahydrodibenzo[b,f]pyrrolo[3,4 d] azepine, M.P. 105- 107. 2 g. ofthe obtained base are dissolved in 20 ml. of acetone and a solution of0.87 g. of oxalic acid in 5 ml. of anhydrous ethanol is added, whereuponthe oxalate crystallizes out, M.P. (after recrystallization fromethanol) 192-194".

Example 6 (a) 0.64 g. of diborane, freshly prepared from 2.6 g. ofsodiumboro'hydride and 13 g. of borontrifluorideetherate (G. Zweifel andHG. Brown, Organic Reactions, vol. XIII, page 32) are introduced withnitrogen into a solution of 13.5 g. of2-ethy1-8-acetyl-1,2,3,S-tetrahydrodibenzo[b,f]pyrrolo[3,4-d]azepine in70 ml. of anhydrous tetrahydrofuran, whilst the temperature ismaintained between and by ice cooling. The mixture was then stirred forone hour at 0-5 and a further hour at -25". ml. of 10% sodium phosphatesolution are then added dropwise and the tetrahydrofuran then evaporatedin a rotary evaporator. The residue is heated to boiling under refluxfor one hour with 300 ml. of 4 N hydrochloric acid, then cooled to 20and rendered basic to phenophthaline with concentrated sodium hydroxide.The precipitated base is extracted with ether. The ethereal solution iswashed with water, dried over potassium carbonate and concentrated to asmall volume, whereupon the 2,8 diethyl 1,2,3,8tetrahydro-dibenzo[b,f]pyrrolo [3,4-d]azepine crystallizes out. Thecrude product is recrystallized from ethanol, M.P. 100-102. 5.8 g. ofthe obtained base are dissolved in ml. of anhydrous acetone and 4 ml. of5 N anhydrous ethanolic hydrogen chloride solution are added, whereuponthe hydrochloride crystallizes out; M.P. after recrystallization fromisopropanol, 267-271" (decomposition).

Example 7 (a) 22 g. of2-allyl-8-methyl-l,2,3,8-tetrahydro-dibenzo[b,f]pyrro1o[3,4-d]azepineare dissolved in 250 ml. of anhydrous benzene and boiled under reflux. Asolution of 9.5 g. of ethylchloroformate in 1 00 ml. of anhydrousbenzene is added dropwise to the reaction mixture within 30 minutes andthe allylchloride formed simultaneously distilled off. After the end ofthe dropwise addition, the mixture is boiled for a further hour underreflux, then cooled to room temperature.

The benzene solution is washed with 2 N hydrochloric acid and then withwater, dried over sodium sulphate and concentrated in vacuo to a smallvolume, whereupon the Z-carbethoxy-S-methyl 1,2,3,8tetrahydro-dibenzo[b,f] pyrrolo[3,4-d]azepine, M.P. 129-131",crystallizes out.

(b) 18 g. ofZ-carbethoxy-S-methyld,2,3,8-tetrahydrodibenzo[b,f]pyrrolo[3,4-d]azepineare boiled for six hours under reflux with a solution of 18 g. ofpotassium hydroxide in 180 ml. of anhydrous ethanol. The ethanol is thendistilled oiT from the reaction mixture in a rotary evaporator. Theresidue is taken up with 200 ml. of water and ether. The etherealsolution is stirred with ml. of 2 N hydrochloric acid, whereupon the8-methyl- 1,2,3,8 tetrahydro-dibenzo[b,f]pyrrolo[3,4-d]azepinehydrochloride precipitates. After filtering under suction and washingwith 2 N hydrochloric acid the crude product is dried in a vacuumcabinet and then recrystallized from ethanol, M.P. 274-278(decomposition).

Example 8 Analogously to Examples 7 (a) and (b), the followingintermediate and end products are prepared.

(a) From 13.8 g. of 2-allyl-1,2,3,8-tetrahydro-dibenzo-[b,f]pyrrolo[3,4-d1azepine and 5.5 g. of ethyl chloroformate, theintermediate product 2-carbethoxy-1,2,3,8- tetrahydrodibenzo[b,f]pyrrolo[3,4 d]azepine (crude product); and by subsequentsaponification the end product1,2,3,X-tetrahydro-dibenzo[b,f]pyrr0l0[3,4-d1azepine, M.P. 222-224 (frombenzene); hydrochloride, M.P. 261-265 (decomposition) (from ethanol).

Example 9 10 g. of 2-ethyl-1,2,3,S-tetrahydro-dibenzo[b,f]pyrrolo-[3,4-d]azepine and 100 m1. of 99% of formic acid are boiled under refluxfor 2 hours with stirring.

The excess formic acid is then evaporated in vacuo from the reactionmixture. The residue is dissolved in water, the base precipitated by theaddition of concentrated ammonia and taken up in ether. The etherealsolution is washed with water, dried over potassium carbonate andevaporated. The residue, 2-ethyl-8-formyl-1,2,3,8-tetrahydro-dibenzo[b,f]pyrrolo[3,4d]azepine is a viscous oil as crudeproduct. 10 g. of the obtained base are dissolved in 30 ml. of absoluteacetone and 6.9 ml. of 5 N anhydrous ethanolic hydrogen chloride areadded, whereupon the hydrochloride crystallizes out. Afterrecrystallization from methanol, the substance melts at 245-250(decomposition).

The following prescriptions further illustrate the production oftablets, drages, capsules, suppositories and ampoules:

Example 10 250 g. of2-ethyl-1,2,3,8-tetrahydro-dibenzo[b,f]pyrrolo[3,4-d]azepinehydrochloride are mixed together with 175.80 g. of lactose and 169.70 g.of potato starch. The mixture is moistened with an alcoholic solution of10 g. of stearic acid, granulated through a sieve and dried. g. ofpotato starch, 200 g. of talcum, 2.50 g. of magnesium stearate and 32 g.of colloidal silicon dioxide are mixed in and the mixture is pressed toform 10,000 tablets each weighing 100 mg. and each containing 25 mg. ofactive substance. Optionally, the tablets can be provided with groovesfor finer adjustment of the dosage amount.

Example 11 A granulate is produced from 250 g. of 2-ethyl-1,2,3,8-tetrahydro dibenzo[b,f]pyrrolo[3,4 d]azepine hydrochloride, 175.90 g. oflactose and the alcoholic solution of 10 g. of stearic acid. After beingdried, the granulate is mixed with 56.60 g. of colloidal silicondioxide, g. of talcum, 20 g. of potato starch and 2.50 g. of magnesiumstearate, and the mixture is pressed into 10,000 drage cores. These aresubsequently coated with a concentrated syrup made from 50228 g. ofcrystallized saccharose, 6 g. of shellac, 10 g. of gum arabic, 0.22 g.of dyestutf and 1.5 g. of titanium dioxide, and dried. The obtaineddrages each weigh 120 mg. and each contain 25 mg. of active substance.

1 1 Example 12 To produce 1000 capsules each containing 25 mg. of activesubstance, 25 g. of 2-propyl-1,2,3,8-tetrahydrodibenzo[b,f]pyrrolo[3,4d]azepine hydrochloride are mixed with 248.0 g. of lactose. The mixtureis evenly moistened with an aqueous solution of 2.0 g. of gelatine andis then granulated through a suitable sieve (e.g. Sieve No. IIIaccording to Ph. Helv. V). The granulate is mixed with 10.0 g. of driedmaize starch and 15.0 g. of talcum. The obtained mixture is uniformlyfilled into 1000 hard gelatine capsules, size 1.

Example 13 Example 14 A solution of 25 g. of2-ethyl-8-methyl-1,2,3,8-tetrahydro-dibenzo['b,f]pyrrolo[2,3d]azepine-hydrochloride in one litre of water is filled into 1000ampoules and sterilized. An ampoule contains a 2.5% solution of 25 mg.of active substance. ,i

What we claim is: 1. A compound of the formula H BrBrH N 1'11 wherein Ris methyl, ethyl, propyl, lower alkanoyl, benzoyl, lower alkoxycarbonylor phenoxycarbonyl.

References Cited UNITED STATES PATENTS 3/ 1970 Schindler et a1. 260-239ALTON D. ROLLINS, Primary Examiner

